The Sphingolipid Pathway in Colon Cancer Chemoprevention

描述（由申请人提供）：本项目的长期目标是确定鞘脂途径在结肠癌发生中的作用，并将该途径的要素确定为有效结肠癌化学预防的新靶点。结直肠癌是美国癌症相关死亡的第二大原因;因此，确定新型有效的药物预防癌症策略至关重要。越来越多的证据表明，饮食因素，特别是脂肪（脂质），在结肠癌发生中很重要。具有生物活性的鞘脂可能是调节炎症的前列腺素途径的关键，在结肠癌发病机制中具有重要意义。鞘脂代谢物如神经酰胺、鞘氨醇和鞘氨醇1-磷酸（S1 P）是一类新的调节细胞增殖、分化和存活的脂质信使。鞘氨醇激酶1（SK 1），磷酸化鞘氨醇形成S1 P的酶，是鞘脂介导功能的关键调节因子，因为它不仅产生促生长、抗凋亡信使S1 P，而且降低促凋亡神经酰胺和鞘氨醇的水平。我们的实验室发现，SK 1和S1 P介导细胞因子诱导的环氧合酶-2（考克斯-2）表达和前列腺素E2（PGE 2）产生，RNA干扰（RNAi）下调SK 1可抑制细胞因子诱导的考克斯-2表达和PGE 2产生，S1 P可刺激HT-29人结肠癌细胞考克斯-2表达和PGE 2产生。大鼠肠上皮细胞SK 1过表达增加考克斯-2表达。值得注意的是，SK 1在包括腺瘤和腺癌的人结肠肿瘤中上调。我们最近证明，SK 1缺乏显着减少结肠肿瘤，包括癌前病变，腺瘤和癌症诱导的氧化偶氮甲烷（AOM），一个既定的结肠致癌物在啮齿动物。基于这些初步数据，我们推测SK 1/S1 P通路可能在结肠癌发生中起关键作用，并构成结肠癌化学预防的新靶点。为了研究这一概念，我们提出以下具体目标：1）评估SK 1/S1 P通路在结肠癌发生中的作用; 2）确定SK 1/S1 P通路在调节考克斯-2表达中的作用和机制; 3）评估抑制SK 1/S1 P通路在结肠癌化学预防中的优势。从该项目中获得的结果将为SK 1/S1 P通路在结肠癌发生中的作用提供重要的见解，并确定基于机制的结肠癌化学预防的新靶点，从而导致未来利用SK 1/S1 P通路在结肠癌发生中的转化研究。公共卫生相关性：最常见的可预防癌症是结直肠癌。我们发现鞘脂通过调节炎症在结肠癌中发挥着关键作用。在这个项目中，我们研究鞘脂途径是否介导结肠癌的发展，我们试图将实验室结果转化为床边临床化学预防措施。

DESCRIPTION (provided by applicant): The long-term goal of this project is to define the role of sphingolipid pathway in colon carcinogenesis and to establish elements of this pathway as novel targets for effective colon cancer chemoprevention. Colorectal cancer is the 2nd leading cause of cancer-related deaths in the US; thus, identification of novel, effective pharmacological cancer-prevention strategies is essential. Accumulating evidence suggests that dietary factors, especially fat (lipids), are important in colon carcinogenesis. Bioactive sphingolipids may be key in regulating the prostanoid pathway of inflammation, significant in colon cancer pathogenesis. Sphingolipid metabolites such as ceramide, sphingosine, and sphingosine 1-phosphate (S1P) are a new class of lipid messengers that regulate cell proliferation, differentiation, and survival. Sphingosine kinase 1 (SK1), the enzyme that phosphorylates sphingosine to form S1P, is a critical regulator of sphingolipid-mediated functions, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro- apoptotic ceramide and sphingosine. Our laboratory found that SK1 and S1P mediate cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in response to cytokines, and that SK1 downregulation by RNA interfering (RNAi) inhibits COX-2 expression and PGE2 production induced by cytokines, and S1P stimulates COX-2 expression and PGE2 production in HT-29, human colon cancer cells. SK1 overexpression in rat intestinal epithelial cells increases COX-2 expression. It is noteworthy that SK1 is upregulated in human colon tumors including adenomas and adenocarcinomas. We recently demonstrated that SK1 deficiency significantly reduces colon tumors including preneoplastic lesions, adenomas and cancers induced by azoxymethane (AOM), an established colon carcinogen in rodents. Based on these preliminary data, we hypothesize that the SK1/S1P pathway may play a pivotal role in colon carcinogenesis and constitute a novel target for chemoprevention against colon cancer. To investigate this concept, we propose the following Specific Aims: 1) Assess the role of the SK1/S1P pathway in colon carcinogenesis; 2) Determine the role and mechanism of the SK1/S1P pathway in regulating COX-2 expression; and 3) Assess the advantages of inhibition of the SK1/S1P pathway in colon cancer chemoprevention. The results obtained from this project will provide important insights into the role of the SK1/S1P pathway in colon carcinogenesis and identify novel targets for mechanism-based colon cancer chemoprevention, leading to future translational research exploiting the SK1/S1P pathway in colon carcinogenesis. PUBLIC HEALTH RELEVANCE: The most common preventable cancer is colorectal cancer. We found that sphingolipids play a pivotal role in colon cancer by regulating inflammation. In this project, we examine whether the sphingolipid pathway mediates development of colon cancer and we attempt to translate the bench results to bed-side clinical chemopreventive measures.